This project proposes the identification, optimization, and characterization of small molecules that affect protein-protein and protein-DNA interactions in the Myc and the beta-catenin-LEF networks. The project also proposes identification and development of anticancer compounds from novel combinatorial chemical libraries. The work is based on discoveries made during the past funding cycle which include the identification of the first small molecule inhibitors of Myc-Max dimerization, inhibitors of LEF-dependent transcription, and compounds that interfere with the growth of cancer cells. The project depends on strong collaboration with the laboratory of Dr. Boger in the area of chemistry and with Dr. Cheresh in the area of animal testing. The following are the specific aims: (1) Identify and characterize small molecules that inhibit Myc-Max dimerization. (2) Identify and characterize small molecules that stabilize interaction of Myc network proteins. (3) Identify and characterize small molecules that specifically inhibit LEF-dependent transcription. (4) Screen primary and analog combinatorial chemical libraries for compounds that are selectively active against cancer cells and characterize these compounds.